1. Field of the Invention
The present invention relates to a fast-acting delivery system for delta-9-tetrahydrocannabinol (dronabinol) to improve bioavailability. More particularly, it provides a stable composition for delivery by inhalation to the lungs, and subsequently to the bloodstream, the composition comprising an a therapeutically effective amount of delta-9-tetrahydrocannabinol (also known as xe2x80x9cdelta-9-THCxe2x80x9d) and a pharmaceutically-acceptable semiaqueous solvent.
2. Statement of the Related Art
Delta-9-tetrahydrocannabinol is currently approved by regulatory authorities for use as an antiemetic in cancer chemotherapy as well as an appetite stimulant for patients inflicted with the AIDS virus. The product is currently marketed under the name MARINOL(copyright) (dronabinol) as an oral soft gelatin capsule in which the drug substance is dissolved in sesame oil.
Bioavailability of the current formulation ranges from 10-20% due to a high first pass metabolism associated with oral administration. The current formulation has an onset of action ranging from 0.5 to 1 hour. It would be desirable to improve bioavailabity and quicken onset of action for the above indications as well as for the treatment of alternative conditions, such as spinal cord spasticity, glaucoma; and Alzheimer""s disease. Alternative routes previously suggested to overcome oral delivery limitations include the administration of drugs (including delta-9-tetrahydrocannabinol) through the inhalation route. It has been demonstrated in the literature, for example, that smoking marijuana cigarettes (the main constituent being dronanbinol, i.e., delta-9-THC) has shown improved bioavailability (60-70%). However, there are obvious disadvantages relating to smoking marijuana, including raw material impurities, depression of alveolar macrophage activity, and bronchial irritation. Another approach suggested in initial reports at a meeting on Feb. 24, 1998, sponsored by the Institute of Medicine, National Academy of Sciences, Division of Neuroscience and Behavioral Health in Washington, D.C., was to study and use particle size data developed in a conventional nebulizer system to try to enhance bioavailability of delta-9-tetrahydrocannabinol after deep lung route of administration. Among the suggested routes of administration suggested by the prior art are those using aerosol formulations to be inhaled as described in Volicer, U.S. Pat. No. 5,804,592, granted Sep. 8, 1998, based on Provisional Application priority May 7, 1997. However, as presently advised, there has been no prior disclosure of experiments which used formulations comprising delta-9-tetrahydrocannabinol and semiaqueous solvents comprising judiciously selected volumetric ratios of alcohol, water and pharmaceutically-acceptable glycols to enhance partitioning, and no evidence of enhanced bioavailability in warm-blooded animals, including humans, has been known for such compositions prior to the present invention. It still remains desirable, therefore, to develop a new safe, fast acting delivery system for delta-9-tetrahydrocannabinol to improve bioavailability, and such a system is the subject matter of the present invention.
In accordance with the present invention there are provided stable compositions for rapid delivery by inhalation to the lungs, and subsequently to the bloodstream, the compositions comprising a therapeutically effective amount of delta-9-tetrahydrocannabinol in a pharmaceutically-acceptable semiaqueous solvent comprising an alcohol, water and a glycol, in relative volumetric amounts sufficient
(i) to aerosolize the composition to a mean mass median aerodynamic diameter in the range of from about 1 up to about 10 xcexcM; and
(ii) to enhance partitioning by producing a stable clear solution near the solubility point of the delta-9-tetrahydrocannabinol.
Among the preferred features of the invention are such compositions wherein
the delta-9-tetrahydrocannabinol comprises from about 0.1 to about 200 mg/mL, and especially 25 and 50 mg/mL;
the solvent comprises ethanol, water and propylene glycol;
the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from 10-70:10-30:20-80, respectively, having a combined total of 100;
the volumetric ratios of ethanol:water:propylene glycol are selected from those in the range of from 10-70:10:20-80, respectively, having a combined total of 100;
the volumetric ratios of ethanol:water:propylene glycol are 35:10:55, respectively, having a combined total of 100.
Also contemplated by the present invention are sterile or preserved sealed unit- and/or multi-unit dosage forms of delta-9-tetrahydrocannabinol comprising a container and a stable composition for rapid delivery by inhalation to the lungs and subsequently to the bloodstream, as first defined above, and especially those wherein the container comprises Type I Amber Glass with a suitable liner.
Numerous experiments have shown that the drug formulation is critical for delta-9-tetrahydrocannabinol to be effectively delivered to the lung rapidly. It has been discovered that the formulations of the present invention must be stable, aerosolize to a particle size less than or equal to 10 xcexcM to reach the lung, and the drug must readily partition out of the delivery system in order to transport across biological membranes and reach the blood stream.
The physico-chemical characteristics of delta-9-tetrahydrocannabinol raw drug material lend themselves to various formulations, including solutions. Delta-9-tetrahydrocannabinol is virtually insoluble in water (0.003 g/mL). It is known that the drug substance is extremely lipophilic, with a reported oil/water coefficient of 9,400,000 (Garret and Hunt, Journal of Pharmaceutical Sciences, Vol. 63, No. 7, pages 1056-1064, 1974; and Thomas et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 255, No. 1, pages 624-630, 1990). These factors have been considered in developing the compositions of this invention.
Also critical to the present invention is the need for selecting substances which will release the drug for absorption or partition it from the dosage form. The lipophilic nature of delta-9-tetrahydrocannabinol suggests that formulations made primarily of lipophilic excipients such as oils, such as sesame seed oil, currently approved for oral unit dosage use, would not be desirable because the drug would not partition readily. In the case of oily excipients, delta-9-tetrahydrocannabinol would have a strong affinity for the formulation and would slowly partition out, resulting in slow absorption, exactly the problem sought to be avoided.
Semiaqueous solutions, that is combinations of organic solvents with small, effective amounts of water, lend themselves to making formulations with delta-9-tetrahydrocannabinol with unexpected increases in partitioning, apparently because the drug has a poor affinity for the water within the formulation. Because of the increased ease of partitioning, once released deeply in the lung from the dosage forms of the present invention, delta-9-tetrahydrocannabinol is able to cross cell membranes rapidly, traverse the alveolar epithelial cells, interstitium, and endothelium to reach the blood stream (Thompson, xe2x80x9cPharmacology of Therapeutic Aerosolsxe2x80x9d Chapter 2, in Pharmaceutical Inhalation Aerosol Technology, Ed. Hickey, Marcel Dekker, Inc. New York, pages 29-37, 1992). As a further advantage, the formulations of delta-9-THC and semiaqueous solvents of the present invention may be aerosolized more easily than oil based systems.
As will be shown hereinafter, delta-9-tetrahydrocannabinol readily dissolves in ethanol and in equal parts of ethanol and propylene glycol to form clear solutions which, for purposes of the present invention, are xe2x80x9cstablexe2x80x9d that is, remain clear through three cycles of freeze/thaw. Such compositions, however, do not meet the ease of partitioning required by the present invention because the delta-9-tetrahydrocannabinol prefers to stay in the organic phase and only slowly releases itself from the dosage form at the intended site of absorption. As will also be described in detail hereinafter, water can be added to the organic phase, and the delta-9-tetrahydrocannabinol is able to remain in solution, near the solubility point of the drug, and, unexpectedly, partitioning is enhanced and in vivo bioavailability is accelerated, especially in comparison with i.v. administration of the same formulation. The experiments have also shown that as the water content of the semiaqueous solvent increases and the ethanol content decreases beyond a certain level, the drug readily falls out of solution, and such unstable formulations no longer function as dosage forms within the scope of the invention.
The citation to Thomas, mentioned above, teaches that aerosol particle size has an influence on the deposition pattern of many drugs in the lung. In general, deposition is successful at a mean mass median aerodynamic diameter in the range of from about 1 xcexcM to about 10 xcexcM. For best results in lung delivery, it is known from Thomas that delta-9-tetrahydrocannabinol should be targeted for delivery deep in the lung, and this is facilitated by using aerosol particle diameters of less than about 3 xcexcM, a size which is readily, but unexpectedly, obtained with the compositions of the present invention, using conventional nebulizers, as will be shown in the examples which follow, and in conventional metered dose inhalers.
To make the formulations of the present invention, it is preferred, but not essential, to dissolve, per mL of final composition, 1-250 mg of delta-9-tetrahydrocannabinol (dronabinol), USP in 5-95% v/v of ethanol, USP (190 proof), or an obvious equivalent, e.g., isopropanol, in a suitable mixer; to add 20-80% v/v propylene glycol, USP, or an obvious equivalent, such as polypropylene glycol, polyethylene glycol, and the like, and 10-25% v/v purified water and mix, and then filter and transfer to a storage tank. A suitable concentration of delta-9-tetrahydrocannabinol in pharmaceutical compositions for inhalation is 0.05 to 15% (by weight). A preferred concentration is from 0.02 to 5%. A more preferred concentration is from 0.1 to 4%. The formulations of the invention can also include minor but effective amounts of anti-oxidants, surfactants, buffers, sodium chloride, pH adjusting agents, bacteriostats, stabilizers, preservatives, and the like.
To package the formulations of the present invention, the formulations are transferred by conventional means to unit-dose or multi-dose sealed containers, such as ampules and vials, preferably made of amber glass Types I, II and III, more preferably Type I, with a suitable liner.
To use the formulations of the present invention, the quantity of delta-9-tetrahydrocannabinol can vary widely. For example, the amount may be from about 0.001 to 35 mg/kg of body weight administered one to six times per day. However, the dose administered to an animal, particularly a human, should be sufficient to effect a therapeutic response over a reasonable time frame. The dose will be determined by the strength of the particular compositions employed and the condition of the person, as well as the body weight of the person to be treated. The size of the dose also will be determined by the existence, nature and extent of any adverse side-effects that might accompany the administration of a particular composition. A suitable dosage of delta-9-tetrahydrocannabinol for administration by inhalation is 0.01 to 100 mg/kg per day, given in 2-4 divided doses. A preferred dosage is 0.01 to 35 mg/kg per day. A more preferred dosage is 0.05 to 5 mg/kg per day.
The following examples illustrate the present invention. They are not to be construed to limit the claims in any manner whatsoever. Semiaqueous solvent ratios are volumetric, i.e., v/v, and total 100 parts.